As the population ages and therapeutic advances improve life expectancies of chronic diseases, the prevalence of end-stage renal disease (ESRD) inexorably increases. Kidney transplantation is the preferred treatment, but an insufficient organ supply renders dialysis the only treatment option for most patients. Although dialysis outcomes have improved modestly in recent years, annual rates of hospitalizations and mortality remain unacceptably high and quality of life is poor. Starved for therapeutic advances to improve outcomes, the nephrology community has adopted opinion-based clinical practice guidelines for many aspects of ESRD care, including our approach to phosphate control. Current guidelines advocate aggressive treatment of hyperphosphatemia to near normal levels (< 5.0 mg/dl) using dietary phosphate binders and highly restrictive diets; however, because there have been no randomized clinical outcomes trials, the assumed benefits of this approach are unproven, potential harms have not been identified, and the optimal serum phosphate target is unknown. To address this important unmet need, we propose ?HiLo?, a large, cluster-randomized pragmatic trial to be conducted as one of the demonstration projects of the NIH Health Care Systems Research Collaboratory. HiLo will evaluate the effects on important clinical outcomes of liberalizing serum phosphate target for patients receiving treatment with maintenance hemodialysis. The trial will enroll 4400 patients and will be fully embedded in the clinical care delivery of >100 dialysis facilities owned and operated by three dialysis provider organizations: a large, national for-profit dialysis company, a mid-sized non-profit dialysis company, and an academically-owned regional provider. HiLo will test the hypothesis that liberal control of serum phosphate to target 6?7 mg/dl will yield non-inferior rates of hospitalization compared to the current standard approach of targeting phosphate levels to <5.0 mg/dl. As a secondary objective, HiLo will test for superiority of the different arms on mortality. The HiLo Data Coordinating Center will be based at the Duke Clinical Research Institute (DCRI), a highly experienced academic research organization and the Coordinating Center for the Collaboratory. The project will be implemented in two phases ? a UG3 planning phase and a UH3 implementation phase ? each of which has specific milestones. In addition to addressing a question of high clinical relevance in ESRD, HiLo will advance the field of pragmatic trials through several innovations: 1) answering a pressing clinical question rather than evaluating strategies to enhance implementation of a proven therapy; 2) using a novel electronic approach for patient-level consent to enable pragmatic evaluation of a ?more than minimal risk? intervention for the first time in ESRD; and 3) providing a precedent for a non-mortality primary endpoint in ESRD trials. Given the importance of the trial question to patients, clinicians, dialysis providers, and payers, and the ?real-world? approach to testing the intervention, the findings of HiLo will be rapidly implemented and readily sustained upon completion of the trial. Additionally, and importantly, HiLo will pave the way for future pragmatic trials in ESRD and more broadly.